Molecular Virology of Hepatitis B Virus

 

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Hepatitis B virus (HBV) has evolved a unique life cycle that results in the production of enormous viral loads during active replication without actually killing the infected cell directly. Because HBV uses reverse transcription to copy its DNA genome, mutant viral genomes emerge frequently. Particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antiviral drugs), readily select out these escape mutants. Which particular viral mutations or combination of mutations directly affect the clinical outcome of infection are not known. Further studies are clearly needed to identify the pathogenic basis and clinical sequelae arising from the selection of these mutants.

REFERENCES

• 1 Guidotti L G, Rochford R, Chung J et al.. Viral clearance without destruction of infected cells during acute HBV infection.  Science. 1999;  284 825-829
  CrossrefPubMedSearch in Google Scholar
• 2 Nayersina R, Fowler P, Guilhot S et al.. HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection.  J Immunol. 1993;  150 4659-4671
  PubMedSearch in Google Scholar
• 3 Rehermann B, Fowler P, Sidney J et al.. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis.  J Exp Med. 1995;  181 1047-1058
  CrossrefPubMedSearch in Google Scholar
• 4 Penna A, Del Prete G, Cavalli A et al.. Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B.  Hepatology. 1997;  25 1022-1027
  CrossrefPubMedSearch in Google Scholar
• 5 Webster G J, Reignat S, Maini M K et al.. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms.  Hepatology. 2000;  32 1117-1124
  CrossrefPubMedSearch in Google Scholar
• 6 Ferrari C, Penna A, Giuberti T et al.. Intrahepatic, nucleocapsid antigen-specific T cells in chronic active hepatitis B.  J Immunol. 1987;  139 2050-2058
  PubMedSearch in Google Scholar
• 7 Barnaba V, Franco A, Alberti A et al.. Recognition of hepatitis B virus envelope proteins by liver-infiltrating T lymphocytes in chronic HBV infection.  J Immunol. 1989;  143 2650-2655
  PubMedSearch in Google Scholar
• 8 Lohr H F, Gerken G, Schlicht H J, Meryer zum Buschenfelde K H, Fleischer B. Low frequency of cytotoxic liver-infiltrating T lymphocytes specific for endogenous processed surface and core proteins in chronic hepatitis B.  J Infect Dis. 1993;  168 1133-1139
  PubMedSearch in Google Scholar
• 9 Jung M, Pape G. Immunology of hepatitis B infection.  Lancet Infect Dis. 2002;  2 43-50
  PubMedSearch in Google Scholar
• 10 Guidotti L G, Chisari F V. Cytokine-mediated control of viral infections.  Virology. 2000;  273 221-227
  CrossrefPubMedSearch in Google Scholar
• 11 Ganem D, Schneider R. Hepadnaviridae: the viruses and their replication. In: Knipe DM, Howley PM Fields Virology. Philadelphia; Lippincott-Raven 2001: 2923-2970
  Search in Google Scholar
• 12 Norder H, Courouce A M, Magnius L O. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes.  Virology. 1994;  198 489-503
  CrossrefPubMedSearch in Google Scholar
• 13 Stuyver L, De Gendt S, Van Geyt C et al.. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness.  J Gen Virol. 2000;  81 67-74
  PubMedSearch in Google Scholar
• 14 Kann M, Bischof A, Gerlich W H. In vitro model for the nuclear transport of the hepadnavirus genome.  J Virol. 1997;  71 1310-1316
  PubMedSearch in Google Scholar
• 15 Ganem D. Hepadnaviridae and their replication. In: Fields BN, Knipe DM, Howley PM Fields Virology, 3rd ed. Philadelphia; Raven 1996: 2703-2737
  Search in Google Scholar
• 16 Tavis J. The replication strategy of the Hepadanaviruses.  Viral Hepatitis Reviews. 1996;  2 205-218
  PubMedSearch in Google Scholar
• 17 Summers J, Mason W S. Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate.  Cell. 1982;  29 403-415
  CrossrefPubMedSearch in Google Scholar
• 18 Okamoto H, Imai M, Kametani M et al.. Genomic heterogeneity of hepatitis B virus in a 54-year-old woman who contracted the infection through materno-fetal transmission.  Jpn J Exp Med. 1987;  57 231-236
  PubMedSearch in Google Scholar
• 19 Lok A S, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal.  Proc Natl Acad Sci USA. 1994;  91 4077-4081
  PubMedSearch in Google Scholar
• 20 Hunt C M, McGill J M, Allen M I et al.. Clinical relevance of hepatitis B viral mutations.  Hepatology. 2000;  31 1037-1044
  CrossrefPubMedSearch in Google Scholar
• 21 Gunther S, Fischer L, Pult I et al.. Naturally occurring variants of hepatitis B virus.  Adv Virus Res. 1999;  52 25-137
  PubMedSearch in Google Scholar
• 22 Akarca U S, Lok A S. Naturally occurring hepatitis B virus core gene mutations.  Hepatology. 1995;  22 50-60
  CrossrefPubMedSearch in Google Scholar
• 23 Carman W F, Zanetti A R, Karayiannis P et al.. Vaccine-induced escape mutant of hepatitis B virus.  Lancet. 1990;  336 325-329
  CrossrefPubMedSearch in Google Scholar
• 24 Carman W F, Trautwein C, van Deursen F J et al.. Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis.  Hepatology. 1996;  24 489-493
  PubMedSearch in Google Scholar
• 25 Stuyver L J, Locarnini S A, Lok A et al.. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region.  Hepatology. 2001;  33 751-757
  CrossrefPubMedSearch in Google Scholar
• 26 Angus P, Vaughan R, Xiong S et al.. Resistance to adefovir dipivoxil therapy associated with development of a novel mutation in the HBV polymerase.  Gastroenterology. 2003;  125 292-297
  CrossrefPubMedSearch in Google Scholar
• 27 Lai C L, Dienstag J, Schiff E et al.. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.  Clin Infect Dis. 2003;  36 687-696
  CrossrefPubMedSearch in Google Scholar
• 28 Leung N. Clinical experience with lamivudine.  Semin Liver Dis. 2002;  22(Suppl 1) 15-21
  PubMedSearch in Google Scholar
• 29 Delaney IV W E, Locarnini S, Shaw T. Resistance of hepatitis B virus to antiviral drugs: current aspects and directions for future investigation.  Antivir Chem Chemother. 2001;  12 1-35
  PubMedSearch in Google Scholar
• 30 Ogata N, Fujii K, Takigawa S et al.. Novel patterns of amino acid mutations in the hepatitis B virus polymerase in association with resistance to lamivudine therapy in Japanese patients with chronic hepatitis B.  J Med Virol. 1999;  59 270-276
  CrossrefPubMedSearch in Google Scholar
• 31 Bock C, Tillmann H, Torresi J et al.. HBV polymerase mutants with enhanced replication selected during lamivudine therapy result in sudden onset of liver failure.  Gastroenterology. 2002;  122 264-273
  PubMedSearch in Google Scholar
• 32 Hadziyannis S J, Papatheodoridis G V, Dimou E et al.. Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B.  Hepatology. 2000;  32 847-851
  CrossrefPubMedSearch in Google Scholar
• 33 Papatheodoridis G V, Dimou E, Laras A et al.. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease.  Hepatology. 2002;  36 219-226
  CrossrefPubMedSearch in Google Scholar
• 34 Chen R, Edwards R, Shaw T et al.. Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro.  Hepatology. 2003;  37 27-35
  CrossrefPubMedSearch in Google Scholar
• 35 Wang J H, Lu S N, Lee C M et al.. Fatal hepatic failure after emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis.  Scand J Gastroenterol. 2002;  37 366-369
  CrossrefPubMedSearch in Google Scholar
• 36 Liaw Y-F, Chien R-N, Yeh C-T et al.. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.  Hepatology. 1999;  30 567-572
  CrossrefPubMedSearch in Google Scholar
• 37 De Man R A, Bartholomeusz A, Niesters H GM et al.. The sequential occurrence of viral mutations in a liver transplant recipient re-infected with hepatitis B virus: hepatitis B immune globulin escape, famciclovir non-response, followed by lamivudine resistance resulting in graft loss.  J Hepatol. 1998;  29 669-675
  CrossrefPubMedSearch in Google Scholar
• 38 Soriano V. Hepatitis B virus infection despite receiving lamivudine in one HIV-infected person.  HIV Clin Trials. 2003;  4 77-78
  PubMedSearch in Google Scholar
• 39 Ayres A, Bartholomeusz A, Lau G K et al.. Lamivudine and famciclovir resistant hepatitis B virus associated with fatal hepatic failure.  J Clin Virol. 2003;  27 111-116
  CrossrefPubMedSearch in Google Scholar
• 40 Thibault V, Aubron-Olivier C, Agut H et al.. Primary infection with a lamivudine-resistant hepatitis B virus.  AIDS. 2002;  16 131-133
  CrossrefPubMedSearch in Google Scholar
• 41 Shaw T, Locarnini S. Combination chemotherapy for hepatitis B virus: the path forward?.  Drugs. 2000;  60 517-531
  PubMedSearch in Google Scholar
• 42 Locarnini S, Birch C. Antiviral chemotherapy for chronic hepatitis B infection: Lessons learned from treating HIV infected patients.  J Hepatol. 1999;  30 536-550
  CrossrefPubMedSearch in Google Scholar
• 43 Lewin S R, Ribeiro R M, Walter T et al.. Analysis of hepatitis B viral load decline under potent therapy: complex decay profiles observed.  Hepatology. 2001;  34 1012-1020
  CrossrefPubMedSearch in Google Scholar

 Professor
Stephen Locarnini

Victorian Infectious Diseases Reference Laboratory

10 Wreckyn Street, North Melbourne

Victoria 3051, Australia

Email: stephenlocarnini@compuserve.com

Email: stephen.locarnini@mh.org.au